Derivatives of N-(iminomethy)amines, their preparation,...

Details Derivatives of N-(iminomethy)amines, their preparation,... Derivatives of N-(iminomethy)amines, their preparation,...

2003-07-01

2004-10-26

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S277000, C514S411000, C514S438000, C514S613000, C514S615000, C514S649000, C514S257000, C549S074000, C549S083000, C548S440000, C544S239000

Reexamination Certificate

active

06809090

ABSTRACT:

A subject of the present invention is new derivatives of N-(iminomethyl)amines comprising the aminodiphenylamine, oxodiphenylamine, carbazole, phenazine, phenothiazine, phenoxazine or oxodiphenyl unit in their skeleton. These derivatives have an inhibitory activity on NO-synthase enzymes producing nitrogen monoxide NO and/or an activity which traps the reactive oxygen species (ROS). The invention relates to the derivatives corresponding to general formula (I) defined below, their preparation methods, the pharmaceutical preparations containing them and their use for therapeutic purposes, in particular their use as NO-synthase inhibitors and selective or non selective traps for reactive oxygen species.
Given the potential role of NO and the ROS's in physiopathology, the new derivatives described corresponding to general formula (I) may produce beneficial or favourable effects in the treatment of pathologies where these chemical species are involved. In particular:
Proliferative and inflammatory diseases such as for example atherosclerosis, pulmonary hypertension, respiratory distress, glomerulonephritis, portal hypertension, psoriasis, arthrosis and rheumatoid arthritis, fibroses, angiogenisis, amyloidoses, inflammations of the gastro-intestinal system (ulcerous or non-ulcerous colitis, Crohn's disease), diarrhoea.
Diseases affecting the pulmonary system and airways (asthma, sinusitis, rhinitis).
Cardio-vascular and cerebro-vascular disorders including for example, migraine, arterial hypertension, septic shock, ischemic or hemorragic, cardiac or cerebral infarctions, ischemias and thromboses.
Disorders of the central or peripheral nervous system such as for example neurodegenerative diseases where there can in particular be mentioned cerebral infarctions, sub-arachnoid haemorrhaging, ageing, senile dementias including Alzheimer's disease, Huntington's chorea, Parkinson's disease, Creutzfeld Jacob disease and prion diseases, amyotrophic lateral sclerosis; ocular neuropathies such as glaucoma but also pain, cerebral and bone marrow traumas, addiction to opiates, alcohol and addictive substances, cognitive disorders, encephalopathies, encephalopathies of viral or toxic origin.
Disorders of the skeletal muscle and neuromuscular joints (myopathy, myosis) as well as cutaneous diseases.
Cataracts.
Organ transplants.
Auto-immune and viral diseases such as for example lupus, AIDS, parasitic and viral infections, diabetes and its complications, multiple sclerosis.
Cancer.
Neurological diseases associated with intoxications (Cadmium poisoning, inhalation of n-hexane, pesticides, herbicides), associated with treatments (radiotherapy) or disorders of genetic origin (Wilson's disease).
all the pathologies characterized by an excessive production or dysfunction of NO and/or ROS's.
In all these pathologies, there is experimental evidence demonstrating the involvement of NO or ROS's (
J. Med. Chem
. (1995) 38, 4343-4362
; Free Radic. Biol. Med
. (1996) 20, 675-705
; The Neuroscientist
(1997) 3, 327-333).
Moreover, in earlier patents, the inventors have already described NO Synthase inhibitors and their use (U.S. Pat. Nos. 5,081,148; 5,360,925) and more recently the combination of these inhibitors with products having antioxidant or antiradicular properties (Patent Application PCT WO/09653). They have also described in not yet published Applications other derivatives of amidines or, more recently, derivatives of aminopyridines. These derivatives of amidines or aminopyridines have the characteristic of being both NO Synthase inhibitors and ROS inhibitors.
A subject of the present invention is new derivatives of amidines, their preparation and their use in therapeutics.
The compounds of the invention correspond to general formula (I):
in which
&PHgr; represents a bond or a phenylene radical which can include, in addition to the two chains already represented in general formula (I), up to two substituents chosen from a hydrogen atom, a halogen, an OH group, and a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms;
A represents a
 radical in which R
1
, R
2
, R
3
, R
4
, R
5
represent, independently, a hydrogen atom, a halogen, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or a cyano, nitro or NR
6
R
7
radical,
R
6
and R
7
representing, independently, a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or also a —COR
8
group,
R
8
representing a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or NR
9
R
10
,
R
9
and R
10
representing, independently, a hydrogen atom, the OH group or a linear or branched alkyl radical having 1 to 6 carbon atoms,
R
11
representing a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or a —COR
12
radical,
and R
12
representing a hydrogen atom, the OH group, a linear or branched alkyl radical having 1 to 6 carbon atoms,
or a
 radical in which R
1
, R
2
, R
3
, R
4
, R
5
represent, independently, a hydrogen atom, a halogen, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or a cyano, nitro or NR
6
R
7
radical,
R
6
and R
7
representing, independently, a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or also a —COR
8
group,
R
8
representing a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or NR
9
R
10
,
R
9
and R
10
representing, independently, a hydrogen atom, the OH group or a linear or branched alkyl radical having 1 to 6 carbon atoms,
B represents —CH
2
—NO
2
, a linear or branched alkyl radical having 1 to 6 carbon atoms, carbocyclic or heterocyclic aryl with 5 or 6 members containing 1 to 4 heteroatoms chosen from O, S, N and in particular the thiophene, furan, pyrrole or thiazole radical, the aryl radical being optionally substituted by one or more groups chosen from linear or branched alkyl, alkenyl or alkoxy radicals having 1 to 6 carbon atoms,
or B represents an NR
13
R
14
radical, in which R
13
and R
14
representing, independently, a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms or a cyano or nitro radical, or R
13
and R
14
form with the nitrogen atom a non aromatic heterocycle with five to six members, the elements of the chain being chosen from a group composed of —CH
2
—, —NH—, —O— or —S—;
W does not exist, or represents a bond, or O, S or NR
15
, in which R
15
represents a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms;
X represents a bond or a (CH
2
)
k
—NR
16
—, —O—, —S—, —CO—, —NR
16
—CO—, —CO—NR
16
—, —O—CO—, CO—O—, —NR
16
—CO—O—, —NR
16
—CO—NR
17
— radical,
k representing 0 or 1;
Y represents a bond or a radical chosen from the —(CH
2
)
m
—, —(CH
2
)
m
—O—(CH
2
)
n
—, —(CH
2
)
m
—S—(CH
2
)
n
—, —(CH
2
)
m
—NR
18
—(CH
2
)
n
—, —(CH
2
)
m
—NR
18
—CO—(CH)
n
—, —(CH
2
)
m
—CO—NR
18
—(CH
2
)
n
—, —(CH
2
)
m
—Q—(CH
2
)
n
— radicals,
Q representing piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-oxypiperidine or 4-aminopiperidine radicals, m and n being integers from 0 to 6;
R
16
, R
17
and R
18
represent, independently, a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms;
or are salts of the products mentioned previously.
By linear or branched alkyl having 1 to 6 carbon atoms, is meant in particular the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl radicals. By linear or branched alkoxy having 1 to 6 carbon atoms, is meant the alkyl radical of which has the meaning indicated previously. Finally, by halogen, is meant fluorine, chlorine, bromine or iodine atoms.
Preferably, the compounds according to the invention are the compounds of general formula (I) such that:
A represents a
 radical in which R
1
, R
2
, R
3
, R
4
, R
5
r

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